Aerosols for the delivery of therapeutic agents to the respiratory tract have been described, for example, Adjei, A. and Garren, J. Pharm. Res., 7:565-569 (1990); and Zanen, P. and Lamm, J.-W. J., Int. J. Pharm., 114:111-115 (1995). The respiratory tract encompasses the upper airways, including the oropharynx and larynx, followed by the lower airways, which include the trachea followed by bifurcations into the bronchi and bronchioli. The upper and lower airways are called the conducting airways. The terminal bronchioli then divide into respiratory bronchioli which then lead to the ultimate respiratory zone, the alveoli, or deep lung. Gonda, I., “Aerosols for delivery of therapeutic and diagnostic agents to the respiratory tract,” in Critical Reviews in Therapeutic Drug Carrier Systems, 6:273-313 (1990). The deep lung or alveoli are the primary target of inhaled therapeutic aerosols for systemic drug delivery.
Inhaled aerosols have been used for the treatment of local lung disorders including asthma and cystic fibrosis (Anderson, Am. Rev. Respir. Dis., 140:1317-1324 (1989)) and have potential for the systemic delivery of peptides and proteins as well (Patton and Platz, Advanced Drug Delivery Reviews, 8:179-196 (1992)).
Relatively high bioavailability of many molecules, including macromolecules, can be achieved via inhalation. Wall, D. A., Drug Delivery, 2:1-20 (1995); Patton, J. and Platz, R., Adv. Drug Del. Rev., 8:179-196 (1992); and Byron, P., Adv. Drug. Del. Rev., 5:107-132 (1990). As a result, several aerosol formulations of therapeutic drugs are in use or are being tested for delivery to the lung. Patton, J. S., et al., J. Controlled Release, 28:79-85 (1994); Damms, B. and Bains, W., Nature Biotechnology (1996); Niven, R. W. et al., Pharm. Res., 12(9):1343-1349 (1995); and Kobayashi, S. et al., Pharm. Res., 13(1):80-83 (1996).
However, pulmonary drug delivery strategies present many difficulties, in particular for the delivery of macromolecules; these include protein denaturation during aerosolization, excessive loss of inhaled drug in the oropharyngeal cavity (often exceeding 80%), poor control over the site of deposition, lack of reproducibility of therapeutic results owing to variations in breathing patterns, the frequent too-rapid absorption of drug potentially resulting in local toxic effects, and phagocytosis by lung macrophages.
In addition, many of the devices currently available for inhalation therapy are associated with drug losses. Considerable attention has been devoted to the design of therapeutic aerosol inhalers to improve the efficiency of inhalation therapies. Timsina et al., Int. J. Pharm., 101:1-13 (1995) and Tansey, I. P., Spray Technol. Market, 4:26-29 (1994). Attention has also been given to the design of dry powder aerosol surface texture, regarding particularly the need to avoid particle aggregation, a phenomenon which considerably diminishes the efficiency of inhalation therapies. French, D. L., Edwards, D. A. and Niven, R. W., J. Aerosol Sci., 27:769-783 (1996).
Dry powder formulations (DPF's) are gaining increased interest as aerosol formulations for pulmonary delivery. Damms, B. and W. Bains, Nature Biotechnology (1996); Kobayashi, S., et al., Pharm. Res., 13(1):80-83 (1996); and Timsina, M. et al., Int. J. Pharm., 101:1-13 (1994). Dry powder aerosols for inhalation therapy are generally produced with mean geometric diameters primarily in the range of less than 5 μm. Ganderton, D., J. Biopharmaceutical Sciences, 3:101-105 (1992) and Gonda, I., “Physico-Chemical Principles in Aerosol Delivery,”0 Topics in Pharmaceutical Sciences (1991), Crommelin, D. J. and K. K. Midha, Eds., Medpharm Scientific Publishers, Stuttgart, pp. 95-115, 1992. Large “carrier” particles (containing no drug) have been co-delivered with therapeutic aerosols to aid in achieving efficient aerosolization among other possible benefits. French, D. L., Edwards, D. A. and Niven, R. W., J. Aerosol Sci., 27:769-783 (1996).
Among the disadvantages of DPF's is that powders of fine particulates usually have poor flowability and aerosolization properties, leading to relatively low respirable fractions of aerosol, which are the fractions of inhaled aerosol that deposit in the lungs, escaping deposition in the mouth and throat. Gonda, I., in Topics in Pharmaceutical Sciences, (1991), D. Crommelin and K. Midha, Editors, Stuttgart: Medpharm Scientific Publishers, pp. 95-117 (1992). Poor flowability and aerosolization properties are typically caused by particulate aggregation, due to particle-particle interactions, such as hydrophobic, electrostatic, and capillary interactions. Some improvements in DPF's have been made. For example, dry powder formulations (“DPFs”) with large particle size have been shown to possess improved flowability characteristics, such as less aggregation (Edwards, et al, Science 276:1868-1871 (1997)), easier aerosolization, and potentially less phagocytosis. Rudt, S. and R. H. Muller, J., Controlled Release, 22:263-272 (1992); Tabata, Y. and Y. Ikada, J. Biomed. Mater. Res., 22:837-858 (1988). An effective dry-powder inhalation therapy for both short and long term release of therapeutics, either for local or systemic delivery, requires a method to deliver a DPF to the lungs efficiently, and at therapeutic levels, without requiring excessive energy input.
Nebulizers, such as described by Cipolla et al. (Cipolla et al. Respiratory Drug Delivery VII, Biological, Pharmaceutical, Clinical and Regulatory Issues Relating to Optimized Drug Delivery by Aerosol, Conference held May 14-18, 2000, Palm Springs, Fla., the contents of which are incorporated herein by reference in their entirety), also are employed in pulmonary delivery.
Inhalation devices which can be employed to deliver dry powder formulations to the lungs include non-breath-activated or “multistep” devices. One such device is described in U.S. Pat. No. 5,997,848 issued to Patton et al. on Dec. 7, 1999, the entire teachings of which are incorporated herein by reference. In these devices, the drug formulation is first dispersed by energy independent of a patient's breath, then inhaled.
Inhalation devices that utilize a “single, breath-activated-step” are designed such that they disperse a powder which is immediately inhaled by a subject, i.e., in a single step, for example, a simple dry powder inhaler (see for example, U.S. Pat. Nos. 4,995,385 and 4,069,819).
Other examples of inhalers include but are not limited to the Spinhaler® (Fisons, Loughborough, U.K.) and Rotahaler® (Glaxo-Wellcome, Research Triangle Park, N.C.).
In comparison to “single-step” inhalers, existing “multi-step inhalers” are more complex to operate and tend to be more costly since extra energy is needed to deliver a drug to the lungs. This amount of energy required increases with increasing drug mass. On the other hand, “high efficiency” of drug delivery to the respiratory tract, meaning about 50% of the drug mass initially contained in a drug receptacle, (i.e., the “nominal dose”), is typically only achieved with breath-activated, multi-step inhaler systems. Therefore, patients have until now needed to make a choice between cost/complexity and efficiency of drug delivery. The reason for this trade-off is that existing inhalation methodologies and devices are associated with inherent formulation inefficiencies and/or inherent device design limitations. Such inefficiencies result in unwanted drug loss and elevated overall cost of treatment. In addition, and often as a consequence, existing inhalation devices and methodologies can often fail to deliver to the lung a sufficient (e.g., therapeutic) mass of drug in a single breath. Currently, the amount of drug that can be delivered to the lung in a single breath, via liquid or dry powder inhalers, generally does not exceed 5 mg (Cipolla, et al., Resp. Drug Delivery, VII 2000:231-239 (2000)).
Therefore a need exists for delivering an agent to the pulmonary system wherein at least about 50% of the nominal dose of the agent is delivered to the pulmonary system via a single-step inhalation system. A need also exists for delivery of a relatively large mass of an agent, such as, for example, a therapeutic, prophylactic, diagnostic, or prognostic agent. A need also exists for delivery of a relatively large mass of a bioactive agent, in particular, a large mass of inhaled dry powder. A need further exists for methods of delivering to the pulmonary system, in a single step, from a simple breath-activated device, a single, high dose of an agent, such as a bioactive agent.